@LearningEachDaySpot on! This is why some trials have to be...

@LearningEachDay

Spot on! This is why some trials have to be stopped for overhwelming efficacy, because it would be unethical to continue randomising to a placebo or other inferior treatment. And, as you say, the Osiris study showed evidence of efficacy in children in the subgroup analysis. That's a good place to start a Phase 3 trial confirming efficacy in children. So there was a question back then whether it would be ethical to randomise children under 12 to placebo. Opinions may have differed,. But the evidence now is too strong in favour of side-effects free efficacy and a randomised trial in young children should be out of the question. By October 2020 we had the Ph 3 results. Now we also have the long term survival data. It's not that difficult to see the ethical problem that arises.

While I am confident that there will be an approval, I believe it will be conditional on another trial which will be in adults. In its public response to the CRL it was MSB’s stated intention to pursue accelerated approval subject to a condition that it conduct a post approval trial. (see the ASX Announcement of 2 Oct 2020) I can’t see how MSB could credibly resile from the position that I assume it argued for in the Type A meeting with the FDA following the CRL.

As to the recommendation that there be another trial to provide further evidence of the effectiveness of Rem-L, yes, that is what the FDA recommended in the CRL back in Oct 2020. But the middle and the moral/ehthical ground here supports a conditional approval.

It is obvious that the discussions with the FDA would have addressed both the FDA’s recommendation for a further trial, and the potency assay issues. Sure, the FDA would not have said in its meetings, yes, we are convinced, there is no need for another trial – that’s not the way a regulatory review works. But the fact that the resubmission was accepted means that the FDA is open to an alternative approach. This is where the long-term survival data and potency assay are crucial.

The FDA Draft Guidelines 2019 (applicable here even though still not finalised) deal with the use of single arm trials as follows:

“FDA experts may “fairlyand responsibly” rely on study designs that produce less certainty in somecircumstances when a better design is not feasible or ethical. This may be thecase for life-threatening and severely debilitating diseases with an unmetmedical need, for certain rare diseases, or potentially even for a morecommon disease where the availability of existing treatments makes certaindesign choices infeasible or unethical. FDA would not, however, find itresponsible to rely on such design choices in other situations in which, forexample, the drug will be used for a less serious disease and greater certaintyabout benefits and risks is needed, or in cases where designs providing morecertainty are possible. In all cases, FDA must reach the conclusion thatthere is substantial evidence of effectiveness to approve a drug; however, thedegree of certainty supporting such a conclusion may differ, depending onclinical circumstances (e.g., severity and rarity of the disease and unmetmedical need).

This reflects thelongstanding awareness that, in certain settings, a somewhat greater risk (comparedto placebo-controlled or other randomized superiority trials) of false positiveconclusions – and therefore less certainty about effectiveness – may beacceptable, when balanced against the risk of rejecting or delaying themarketing of an effective therapy, as described below for an unmet medicalneed. The data supporting effectiveness could, despite the greater risk oferror, support a conclusion that there is substantial evidence of effectiveness.Therefore, when selecting a trial design, a sponsor should consider thespecific clinical circumstance, including the severity of the disease, unmetmedical need (e.g., whether there is available therapy), the rarity of thedisease, and whether it is feasible and ethical to conduct a randomizedconcurrently controlled superiority trial.” (My emphasis)

Let’s remember Ruxolitinib was granted approval for sraGvHD in patients over 12 on the basis of a open label/single arm trial. Here is an analysis that appeared in Oncologist (2020;25:e328-e334) of the risk -benefit assessment behind that approval:

Lookat the criteria applied:

· Serious disease/poorprognosis;

· No approvedtherapies;

· Single arm study (Study271/Reach 1) showed durable response;

· Major risks (eghemorrage) could be addressed through labelling.

Applythese same criteria here and there is a very stong case for approval. We tick even box and, in the case of the last of them, there is not the slightest suggestion of any safety concerns.

Sure, the FDA’s CRL came as a huge surprise given the 9-1 AdCom vote. It has made me ultra caution this time around. But the rejection must be viewed in light of the use of a single arm trial, the failed Osiris trials (missing primary endpoint), and inadequacies in the potency assays that were previously relied on by MSB. I’m confident the latter issue has been resolved, and in a way that provides a compelling explanation for the failure of the Osiris trials. At the very least they can be put aside on the basis that the potency level of the product was less than what it was for the Phase 3. As to the use of a single arm trial, this is where the FDA’s own guidelines (see above) and the Adcom vote matter most.

It’s important that people here form their own views based on the available information. Don’t rely on others’ opinions, including those of the naysayers who think that the FDA’s October 2020 recommendation (which they previously mischaracterised as a requirement) implies that there is a substantial risk of another rejection. Of course there is risk -- how large is the risk is for each of us to judge and to weigh up against the potential return if approval is granted. To the extent I am not familiar with all the new information submitted to the FDA (and none of us here are) I am confident that Krause is, and I regard his recent purchase as a very strong signal in favour of an approval.